The federal government has set a Healthy People 2020 goal of a 70.5% screening rate for colorectal cancer (CRC), but almost half of eligible U.S. adults are not up to date on their screenings. Among minority and low-income populations, the CRC screening rate is extremely low. To address this disparity, we will develop and test a culturally tailored, health care system-based program to improve CRC screening rates in OCHIN, a community-based collaborative network of more than 200 Federally Qualified Health Centers (FQHCs). Racial and ethnic minorities, along with low-income and medically underserved populations, increasingly receive their primary care at FQHCs, which serve nearly 19 million patients annually throughout the United States. OCHIN is the largest national FQHC network. Its integrated electronic health record system combining medical, laboratory, and claims data will serve as a novel and robust data source for our study. In Phase I (Year 01), we will pilot-test an evidence-based approach to improving participation in CRC screening in two OCHIN FQHCs. This phase will include an assessment of the intervention's feasibility, effectiveness, and cost. In Phase II (Years 02-05), we will conduct a comparative effectiveness pragmatic clinical trial, using a mixed-methods approach to evaluate the adoption, implementation, and maintenance of our CRC screening program designed explicitly for FQHC clinics. Throughout the project, we will work with a diverse planning advisory group of OCHIN clinicians and patients, community representatives, state policy makers, and researchers, using principles of Community-Based Participatory Research. Because OCHIN is the largest single FQHC network and serves patients who are diverse in race, ethnicity, and insurance status, our results will play a transformative role in accelerating CRC screening research in underserved populations. Our program will expand meaningful use of electronic health information; synergistically meet national goals to improve cancer screening rates, address health disparities, and reduce health care costs; and act as a catalyst for future systems-based approaches to improve care delivery in FQHCs and other health systems.